1. Field of the Invention
The invention relates to new 4-substituted azetidinones having the formulae I and II: ##STR2## with R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and X defined hereafter, as intermediates for the preparation of carbapenem and carbacephem antibacterials through the utilization of an acid mediated ring closure reaction shown to form carbapenems III and carbacephems IV with R.sup.1 -R.sup.5 defined hereafter. ##STR3##
2. Description of the Prior Art
A number of carbapenem derivatives containing the basic structure (and numbering scheme) ##STR4## have been disclosed in the literature to have utility as antibacterial agents. The 2-substituted carbapenems are known to be effective antibacterials. For example, T. H. Salzmann et al., in "Recent Advances in the Chemistry of .beta.-Lactam Antibiotics," P. H. Bentley and R. Southgate eds., Royal Society of Chemistry, 1989, pp. 171-189 discloses 2-alkyl-3-carboxycarbapenems ##STR5## to have antibacterial activity where alkyl is defined therein. R. B. Sykes et al., in "Antibiotic Inhibitors of Bacterial Cell Wall Biosynthesis," D. J. Tipper ed., Pergamon Press, 1987, pp. 184-188 describes 2-substituted-3-carboxy carbapenems ##STR6## having antibacterial activity, where S-alkyl is defined therein.
In U.S. Pat. No. 4,707,547 2-amino-substituted-3-carboxy carbapenems ##STR7## are disclosed to have antibacterial properties, where amine is defined therein. 2-Substituted-3-carboxy carbapenems that have substituents bonded to the 2-position of the carbapenem ring through carbon, sulfur or nitrogen all have antibacterial properties of interest.
General methods to prepare the carbapenem nucleus are limited. In U.S. Pat. No. 4,350,631 a rhodium (II) acetate catalyzed ring closure of the .alpha.-diazo-.beta.-ketoester produces the 2-oxo-3-carboxy carbapenem nucleus. This product serves as a key intermediate for the preparation of other 2-substituted-3-carboxy carbapenems. ##STR8##
Another general method to synthesize the carbapenem nucleus is found in European Patent Application No. 83301073.9 (Beecham). The carbapenem nucleus is synthesized via an intramolecular Wittig reaction shown below using a specific example (2-thiopyrimidinyl-3-carboxy carbapenem) from this disclosure. This intramolecular Wittig reaction method is also used to prepare 2-alkylsubstituted-3-carboxy carbapenems as demonstrated in European Patent Application No. 89102859.9 (Fujisawa). ##STR9##
H. Wasserman et al., reported in Tetrahedron Letters, Vol. 25, pp. 3747-3750, (1984) a method to make a known carbapenem and carbacepham from the earlier mentioned U.S. Pat. No. 4,350,631. In this disclosure a diketoester is closed to form a 3-hydroxy carbapenem via dehydration with activated molecular sieves. The hydroxyl group in this intermediate must be removed in a reduction step to form the .beta.-ketoester carbapenem that is disclosed in the Merck patent. The Wasserman et al. disclosure provides no teaching or suggestion on the preparation of compounds with general formulae I or II where R.sup.3 is a functionality other than the oxo group utilized therein. Additionally, the Wasserman et al. disclosure provides no teaching for the direct conversion of compounds with formulae I and II to cyclized adducts III and IV respectively. ##STR10##
The object of the present invention is two-fold. The first objective is to provide novel families of 4-substituted azetidinones of formulae I and II via new and general chemical processes. The second objective is to demonstrate the utility of compounds I and II as precursors in a one-step acid mediated cyclization to carbapenem and carbacephem of formulae III and IV respectively.